March 2014
479
Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,
Pyridazines, and Their Fused Derivatives
100 mmol) was added portionwise to this solution with
shaking; each portion is being added after the vigorous
reaction and evolution of fumes have ceased. After complete
addition, the reaction mixture was heated on a boiling water
bath for 1 h, and then allowed to stand overnight. The
crystalline products thus obtained were triturated with ethanol,
filtered off, and then recrystallized from ethanol.
C18H15N5O (317.34): C, 68.13; H, 4.76; N, 22.07. Found: C,
68.18; H, 4.80; N, 22.27.
The reaction of phenacyl-malononitriles 8a,b with hydrazines
in solution: synthesis of 11a–d and 12a–d. A solution of 8a
or 8b (0.01 mol) and hydrazine hydrate or phenyl hydrazine
(0.01 mol) in 25 mL of dioxane was refluxed for 2 h. The
reaction mixture was allowed to cool to room temperature.
The solid precipitate was filtered off, boiled in ethanol where a
part dissolved, filtered while hot, and left to recrystallize. The
insoluble part was recrystallized from DMF/dioxane mixture
(1:1) and identified as 11a–d. The precipitated part from ethanol
was identified as 12a–d. Compounds 11a–d/12a–d were found
to be approximately 1/1 in each case.
2-[2-(4-Methoxyphenyl)-2-oxo-ethyl]-malononitrile 8a. Light
yellow crystals: yield (18.0g, 84%); mp 188–189ꢀC (Lit. [11]
191–192ꢀC); υmax = 2257 (CN), 1684 (CO) cmÀ1; m/z = 213
[M+ À 1]. dH = 3.60 (d, 2H, CH2; J = 4.1 Hz), 3.85 (s, 3H, CH3),
4.35 (t, 1H, CH; J = 4.1Hz), 6.90 and 7.85 (2d, 4H, Ar-H;
J=7.15Hz). dC = 17.77 (d, CH), 39.12 (t, CH2), 55.65 (q, CH3)
112.52 (s, CN), [114.31 (d), 130.66 (d), 131.33 (s), 164.79 (s) Ph
Carbons], 189.80 (s) (C═O). Anal. Calcd for C12H10N2O2 (214.22):
C, 67.28; H, 4.71; N, 13.08. Found: C, 67.35; H, 4.82; N, 13.25.
2-[2-(4-Cyanophenyl)-2-oxo-ethyl]malononitrile 8b. Light
coffee brown crystals: yield (17.8g, 85%); mp 180–182ꢀC;
5-(4-Methoxyphenyl)-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-
3-yl amine 11a. zDirty yellow crystalline solid, yield (0.90 g, 75%)
mp 290–291ꢀC. υmax = 3305, 3215, 3138, 3130 (NH2 and NH) cmÀ1
;
m/z= 243 [M+]. dH =2.40–2.48 (s, 2H, CH2), 3.68 (s, 3H, CH3), 6.80
(br s, 2H, NH2), 7.45–7.82 (2d, 4H, Ar-H; J=7.20 Hz), 8.54 (br s,
1H, NH), 11.63 (br s, 1H, NH). d = 15.48 (t), 55.90 (q), 89.32
(s), 114.15(d), 123.63 (s), 130.4 (d), 132.25 (s), 152.10 (s), 155.65
(s), 164.85 (s). Anal. Calcd for C12H13N5O (243.26): C, 59.25; H,
5.39; N, 28.79. Found C, 59.35; H, 5.24; N, 28.85.
υ
max = 2261 (CN), 2229 (CN), 1691 (CO) cmÀ1; m/z = 209 [M+].
dH = 4.12 (d, 2H, CH2; J = 4.0 Hz), 5.15 (t, 1H, CH; J = 4.0 Hz),
8.03 and 8.20 (2d, 4H, Ar-H; J = 7.15 Hz). dC = 17.89 (d, CH),
39.08 (t, CH2), 114.20 (s, CN), 116.10 (s, CN), [118.14
(s), 128.84 (d), 132.78 (d), 137.90 (s) Ph Carbons], 193.95 (s)
(C═O). Anal. Calcd for C12H7N3O (209.20): C, 68.89; H, 3.37;
N, 20.09. Found: C, 68.75; H, 3.35; N, 20.19.
Preparation of 3,5-diaminopyrazole derivatives 9a–d:
general procedure. A mixture of each of 8a,b (0.01 mol) and
hydrazine hydrate or phenyl hydrazine (0.015 mol) is warmed
under dry conditions on a water bath where a vigorous reaction
took place. Few drops of triethylamine may be added to activate
the reaction. The solid masses formed on standing at room
temperature were triturated with ethanol and then poured onto
cold water and acidified by few drops of conc. HCl. The solid
products so formed were filtered off and recrystallized from
ethanol/dimethylformamide (DMF) mixture (4:1).
4-(3-Amino-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-5-yl)
benzonitrile 11b. Dirty yellow crystalline solid, yield (0.87 g,
73%) mp 293–294ꢀC. υmax = 3325, 3220, 3135, 3132 (NH2 and
NH), 2225 (CN) cmÀ1; m/z = 238 [M+]. dH = 2.42–2.46 (s, 2H,
CH2), 7.47–7.85 (2d, 4H, Ar-H; J = 7.18 Hz), 8.35 (br s, 2H,
NH2), 8.55 (br s, 1H, NH), 11.65 (br s, 1H, NH). Anal. Calcd
for C12H10N6 (238.25): C, 60.50; H, 4.23; N, 35.27. Found
C, 60.56; H, 4.32; N, 35.20.
5-(4-Methoxyphenyl)-2,7-diphenyl-4,7-dihydro-2H-pyrazolo
[3,4-c]pyridazin-3-yl amine 11c.
Brown crystalline solid,
yield (1.25 g, 63%) mp 305–307ꢀC. υmax = 3325–3220 (NH2)
cmÀ1; m/z = 395 [M+]. dH = 2.43–2.48 (s, 2H, CH2), 3.72 (s,
3H, CH3), 8.72 (br s, 2H, NH2), 7.25–7.95 (m, 14H, Ar-H).
Anal. Calcd for C24H21N5O (395.46): C, 72.89; H, 5.35; N,
17.71. Found C, 72.95; H, 5.25; N, 17.60.
2-(3,5-Diamino-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)-
ethanone 9a.
Yellow crystals: yield (1.85 g, 75%); mp
236–237ꢀC; υmax = 3332, 3216, 3118 (NH2 and NH), 1658 (CO)
cmÀ1; m/z =242 [M+ À 4]. dH = 3.80 (s, 2H, CH2), 3.90 (s, 3H,
CH3), 7.25 and 7.65 (2d, 4H, Ar-H; J = 7.12 Hz.), 8.52 (br, 4H,
2NH2), 11.20 (s, 1H, NH). Anal. Calcd for C12H14N4O2 (246.27):
C, 58.53; H, 5.73; N, 22.75. Found: C, 58.65; H, 5.60; N, 22.55.
4-[2-(3,5-Diamino-1H-pyrazol-4-yl)-acetyl]-benzonitrile
4-(3-Amino-2,7-diphenyl-4,7-dihydro-2H-pyrazolo[3,4-c]
pyridazin-5-yl)benzonitrile 11d.
Brown crystalline solid,
yield (1.27 g, 65%) mp 312–314ꢀC.
υ
max = 3325–3225
(br, NH2); 2223 (CN) cmÀ1; m/z = 390 [M+]. dH = 2.45–2.49
(s, 2H, CH2), 6.75–8.15 (m, 16H, Ar-H + NH2). Anal. Calcd for
C24H18N6 (390.44): C, 73.83; H, 4.65; N, 21.52. Found
C, 73.90; H, 4.55; N, 21.40.
9b.
Yellow crystals: yield (1.64 g, 68%); mp 253–255ꢀC;
υ
max = 3335, 3226, 3078 (NH2 and NH), 2225 (CN), 1678
3-Imino-6-(4-methoxyphenyl)-2,3,4,5-tetrahydropyridazine-
4-carbonitrile 12a. Pale yellow crystalline solid, yield (0.78 g,
69%) mp 235–236ꢀC. υmax = 3280, 3190 (NH) and 2231 (CN)
cmÀ1; m/z = 228 [M+]. dH = 1.75–1.80 (d, 2H, CH2; J = 3.6 Hz),
2.40–2.52 (t, 1H, CH; J = 3.6 Hz), 3.92 (s, 3H, CH3), 7.42 (s, 1H,
ring NH), 7.44–7.58 (2d, 4H, Ar-H; J = 7.14Hz), 11.45 (s, 1H,
═NH). dc = 22.54(t), 25.84(d), 54.95(q), 114.54(d), 115.30(s),
123.75(s), 130.16(d), 155.73(s), 163.75(s), 166.54(s). Anal. Calcd
for C12H12N4O (228.25): C, 63.15; H, 5.30; N, 24.55. Found C,
63.12; H, 5.35; N, 24.62.
(CO) cmÀ1; m/z = 241 [M+]. dH = 3.60 (s, 2H, CH2), 4.65
(s, 2H, NH2) 7.40 and 7.80 (2d, 4H, Ar-H; J = 7.10 Hz),
10.30 (s, 2H, NH2), 10.45 (s, 1H, NH). Anal. Calcd for
C12H11N5O (241.25): C, 59.74; H, 4.60; N, 29.03. Found:
C, 59.60; H, 4.65; N, 29.20.
2-(3,5-Diamino-1-phenyl-1H-pyrazol-4-yl)-1-(4-methoxy-
phenyl)-ethanone 9c. Yellow crystals: yield (2.45 g, 76%);
mp 212–213ꢀC; υmax = 3329–3115 (NH2), 1660 (CO) cmÀ1
.
m/z = 322 [M+]. dH = 3.62 (s, 2H, CH2), 3.91 (s, 3H, CH3),
7.15–7.65 (m, 9H, Ar.H), 8.1 (br, 2H, NH2), 8.17 (br,
2H, NH2). Anal. Calcd for C18H18N4O2 (322.36): C, 67.07;
H, 5.63; N, 17.38. Found: C, 67.00; H, 5.55; N, 17.50.
6-(4-Cyanophenyl)-3-imino-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 12b.
Brownish yellow crystalline solid, yield
(0.75 g, 67%) mp 240–242ꢀC. IR: υmax = 3283, 3195 (NH),
2224 and 2232 (2CN) cmÀ1; m/z = 223 [M+]. dH = 1.74–1.79
(d, 2H, CH2; J = 3.5 Hz), 2.41–2.53 (t, 1H, CH; J = 3.5 Hz),
7.40 (s, 1H, ring NH), 7.42–7.65 (2d, 4H, Ar-H; J = 7.12 Hz),
11.48 (s, 1H, NH). Anal. Calcd for C12H9N5 (223.23):
C, 64.56; H, 4.06; N, 31.37. Found C, 64.55; H, 4.15; N, 31.25.
4-[2-(3,5-Diamino-1-phenyl-1H-pyrazol-4-yl)-acetyl]-
benzonitrile 9d. Yellow crystals: yield (2.10g, 66%); mp 242–
243ꢀC; υmax =3335–3138 (NH2), 2227 (CN), 1667 (CO) cmÀ1
;
m/z = 317 [M+]. dH = 3.64 (s, 2H, CH2), 7.25–7.80 (m, 9H, Ar-H),
8.15 (br, 2H, NH2), 8.21 (br, 2H, NH2). Anal. Calcd for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet